Activatable antibodies having non-binding steric moieties and methods of using the same

a technology of steric moieties and antibodies, applied in the field of activated antibodies, can solve the problems of limited therapeutic effectiveness, rapid clearance from the circulation, and limitations of antibody-based therapeutics, and achieve the effect of favorable biodistribution and increased bioavailability

Active Publication Date: 2018-01-02
CYTOMX THERAPEUTICS
View PDF16 Cites 9 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides activatable antibodies with a non-binding steric moiety or binding partner that recruits the non-binding steric moiety. The non-binding steric moiety can interfere with binding of the antibody to the target in an uncleaved state but does not interfere with binding in a cleaved state, allowing for improved biodistribution and reduced toxicity. The activatable antibodies have a long half-life prior to cleavage and once released, the antibody has a shorter half-life to reduce toxicity. The released antibody also exhibits enhanced penetrance at a disease treatment or diagnostic site.

Problems solved by technology

Antibody-based therapies have proven effective treatments for some diseases but in some cases, toxicities due to broad target expression have limited their therapeutic effectiveness.
In addition, antibody-based therapeutics have exhibited other limitations such as rapid clearance from the circulation following administration.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Activatable antibodies having non-binding steric moieties and methods of using the same
  • Activatable antibodies having non-binding steric moieties and methods of using the same
  • Activatable antibodies having non-binding steric moieties and methods of using the same

Examples

Experimental program
Comparison scheme
Effect test

example 1

Construction of a Binding Partner (BP)-Activatable Antibody

[0198]A BP-activatable antibody referred to herein as activatable antibody “ABP-1203-C225,” which includes the albumin-binding peptide (ABP) SA06 (Dennis et al., J. Biol. Chem. 277, 35035 (2002)) linked to the anti-EGFR antibody C225 (Li et al., Cancer Cell 7, 301 (2005)), was made using recombinant DNA technology. Specifically, the following components were used: a nucleic acid molecule encoding the albumin-binding peptide SA06 (QRLMEDICLPRWGCLWEDDF) (SEQ ID NO: 1) fused to a flexible portion (FP1) having the sequence GSSGGSGGSGGSGGGSGGGSGG (SEQ ID NO: 2), a cleavable linker (CL) referred to herein as 1203 having the sequence TGRGPSWV (SEQ ID NO: 3), which is cleaved by human urokinase plasminogen activator (uPA), a second flexible portion (FP2) having the sequence GG, and the N-terminus of the C225 antibody light chain. The BP-activatable antibody was constructed using techniques similar to those described in PCT Internati...

example 2

Affect of Serum Albumin on Binding of a BP-Activatable Antibody to its Target

[0202]A test to compare the abilities of activatable antibody ABP-1203-C225 and C225 parental antibody to bind to EGFR antigen was conducted under various conditions to assess the ability of albumin to block such binding by the activatable antibody. Results are depicted in FIG. 2. Briefly, the parental antibody (C225) or the activatable antibody ABP-1203-C225 (100 nM) was incubated with or without the human protease, urokinase plasminogen activator (uPA; 10 μg / ml, R&D Systems) at 37° C., O / N in uPA digestion buffer (50 mM Tris, pH 7.4, 100 mM NaCl, 1 mM EDTA, and 0.01% Tween-20). Activatable antibody treated with uPA was diluted in binding buffer (TBS (50 mM Tris-HCl, pH 7.4, 150 mM NaCl) plus 2 mM CaCl2) that included 50 mg / ml of various serum albumins (mouse serum albumin (MSA), rat serum albumin (RatSA), or human serum albumin (HuSA) (each being available from Sigma) as indicated, or with non-fat dry mil...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
timeaaaaaaaaaa
physiological temperatureaaaaaaaaaa
pHaaaaaaaaaa
Login to View More

Abstract

The invention relates generally to activatable antibodies and methods of making and using these activatable antibodies in a variety of therapeutic, diagnostic and prophylactic indications.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 663,151, filed Jun. 22, 2012, the contents of which are incorporated herein by reference in their entirety.INCORPORATION OF SEQUENCE LISTING[0002]The contents of the text file named “42652518001US.txt”, which was created on Sep. 20, 2013 and is 32.7 KB in size, are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION[0003]The invention relates generally to activatable antibodies and methods of making and using these activatable antibodies in a variety of therapeutic, diagnostic and prophylactic indications.BACKGROUND OF THE INVENTION[0004]Antibody-based therapies have proven effective treatments for some diseases but in some cases, toxicities due to broad target expression have limited their therapeutic effectiveness. In addition, antibody-based therapeutics have exhibited other limitations such as rapid clearance from the circulation following administration.[00...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & AuthorityPatents(United States)
IPC IPC(8): C07K16/28C07K14/00C07K14/76G01N33/574C07K16/00C07K16/18
CPCC07K16/18C07K16/00G01N33/574C07K16/2863C07K2319/00
InventorLOWMAN, HENRY BERNARDLIU, SHOUCHUN
OwnerCYTOMX THERAPEUTICS